Comparative postantibacterial activities of pefloxacin, ciprofloxacin, and ofloxacin against intracellular multiplication of Legionella pneumophila serogroup 1

Abstract

The inhibitory and postantibacterial activities of pefloxacin, ciprofloxacin, and ofloxacin against virulent Legionella pneumophila serogroup 1 were evaluated in cell-free and cellular models. In the absence of macrophages (with the tissue culture medium alone), bacterial numbers remained unchanged at 24 h in the presence of 0.1 ,ug of pefioxacin, ciprofloxacin, or ofloxacin per ml and 1.0 ,ug of pefloxacin per ml, whereas they were reduced in the presence of 1.0 ,ug of ciprofloxacin or ofioxacin per ml. Experiments to evaluate the postantibacterial effects of these drugs were therefore performed with concentrations of 0.1 ,ug/ml. In the cell-free model, brief exposure (1 h) of bacteria to each antimicrobial agent resulted in a transient decrease in numbers followed by logarithmic growth. In the cellular model, all three drugs (at 0.1 and 1.0 ,ug/ml) inhibited the intracellular multiplication of L. pneumophila. The intracellular postantibacterial effects of 0.1 ,ug of pefloxacin, ciprofloxacin, and ofloxacin per ml, which were left in contact with L. pneumophila-infected human macrophages for 24 h, were evaluated at various times after removal of the drugs. Pefloxacin was found to exhibit a significant inhibitory effect at 72 h, whereas following the removal of ciprofloxacin and ofloxacin, rapid bacterial multiplication occurred, leading to the destruction of the macrophage monolayer within 48 h.Thus, while pefloxacin, ciprofloxacin, and ofloxacin all inhibited the multiplication of L. pneumophila in human monocyte-derived macrophages, only pefloxacin exhibited a prolonged postantibacterial effect.Three new fluoroquinolones, pefloxacin (6, 37), ciprofloxacin (17-19), and ofloxacin (35, 36), have been shown to be more active than erythromycin (6, 37) and josamycin (36) against Legionella pneumophila in cellular and experimental animal infection models. Other new difluorinated and trifluorinated quinolone agents have also been found to be active against L. pneumophila (7, 13, 16, 26, 31). We have previously demonstrated that pefloxacin shows a potent postantibacterial effect (PAE) against virulent L. pneumophila serogroup 1 in guinea pig infection and human monocyte-derived macrophage models (6, 37). Recently, Edelstein and Edelstein (12) have shown that contrary to ciprofloxacin, WIN 57273, a new quinolone antimicrobial agent, inhibits the growth of L. pneumophila grown in guinea pig alveolar macrophages in an irreversible manner.The objective of this study was to evaluate and compare the intracellular PAEs of three quinolones, pefloxacin, ciprofloxacin, and ofloxacin, against L. pneumophila. The drug concentration that would inhibit but not kill the Legionella strain that was used, thus allowing the determination of intracellular PAE, was assessed first in a macrophage-free model. We then compared the intracellular inhibitory activities and PAEs of the three antimicrobial agents in a macrophage model. MATERIALS AND METHODSBacteria. L. pneumophila serogroup 1 (strain Paris CB 81-13) was used in all experiments. T...

In Vitro Activity of Gemifloxacin (SB-265805, LB20304a) against Legionella pneumophila and Its Pharmacokinetics in Guinea Pigs with L. pneumophila Pneumonia

“…The approximate ratios of the cellular-to-extracellular ratios to the MICs for L. pneumophila for each drug tested are 900, 300, 3,000, and 80 for gemifloxacin, levofloxacin, pneumophila but do not correlate with their intracellular activities completely. A prolonged postantibiotic effect in macrophages, as observed in this study for gemifloxacin, has been regularly observed for fluoroquinolone antimicrobial agents and azithromycin tested using these methods (9,10,17,29). Some bacterial strain differences were noted in these experiments, with gemifloxacin and azithromycin appearing more active against intracellular strain F889 in comparison with strain F2111.…”

In vitro activity of levofloxacin against contemporary clinical isolates of Legionella pneumophila, Mycoplasma pneumoniae and Chlamydia pneumoniae from North America and Europe

“…Levofloxacin at 1 mg/L has been shown to have bactericidal activity against intracellular organisms grown in guinea pig alveolar macrophages by reducing the viable counts of two isolates by 2–3 log 10 CFU/mL, and was significantly more effective than erythromycin in the same model [9]. Furthermore, the fluoroquinolones have also been shown to have a significant postantibiotic effect against L. pneumophila [23,24]. Uncontrolled clinical trials have shown that the newer fluoroquinolones, including levofloxacin, were effective in treating both community‐acquired and nosocomial infections [25,26].…”

Inhibitory and bactericidal activities of levofloxacin, ofloxacin, erythromycin, and rifampin used singly and in combination against Legionella pneumophila

“…Erythromycin and ofloxacin at similar concentrations had inhibitory effects, with evidence of regrowth of the organism at 72 h. Because of the frequent addition of rifampin to patients seriously ill with infections caused by L. pneumophila, our time-kill curve studies included fluoroquinolone or erythromycin combinations with The mortality rate among patients with L. pneumophila infections continues to be high, especially in bacteremic, immunocompromised, and intubated patients (8,16,23,29). It is known from previous in vitro studies with and without the inclusion of macrophages that the effect of erythromycin on L. pneumophila is an inhibitory one (2,18,21,24,25,31,38). In vivo comparative drug studies of the doses and lengths of therapy needed in patients with different primary diseases are lacking (8,16,23,(28)(29)(30).…”